Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The suppression and eradication of primary tumors and distant metastases is a major goal of alternative treatment strategies for cancer, such as inhibition of angiogenesis and targeted immunotherapy. We report here a synergy between two novel monotherapies directed against vascular and tumor compartments, respectively, a tumor vasculature-specific antiangiogenic integrin alphav antagonist and tumor-specific antibody-interleukin 2 (IL-2) fusion proteins. Simultaneous and sequential combination of these monotherapies effectively eradicated spontaneous liver metastases in a poorly immunogenic syngeneic model of neuroblastoma. This was in contrast to controls subjected to monotherapies with either an antiangiogenic integrin alphav antagonist or antibody-IL-2 fusion proteins, which were only partially effective at the dose levels applied. Furthermore, simultaneous treatments with the integrin alphav antagonist and tumor-specific antibody-IL-2 fusion proteins induced dramatic primary tumor regressions in three syngeneic murine tumor models, i.e., melanoma, colon carcinoma, and neuroblastoma. However, each agent used as monotherapy induced only a delay in tumor growth. A mechanism for this synergism was suggested because the antitumor response was accompanied by a simultaneous 50% reduction in tumor vessel density and a 5-fold increase in inflammatory cells in the tumor microenvironment. Subsequently, tumor necrosis was demonstrated only in animals receiving the combination therapy, but not when each agent was applied as monotherapy. The results suggest that these synergistic treatment modalities may provide a novel and effective tool for future therapies of metastatic cancer.
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PMID:Synergy between an antiangiogenic integrin alphav antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. 999 69

Solid tumors are dependent on preexisting vasculature and neovascularization for their growth. Successful cancer therapies targeting the tumor vasculature would be expected to block the existing tumor blood supply and to prevent tumor neovascularization. We tested the antitumor activity of experimental therapy with 2 distinct antiangiogenic drugs. Vasostatin inhibits endothelial cell growth and neovascularization, and interleukin-12 (IL-12) targets the tumor vasculature acting through interferon-gamma (IFN-gamma) and the downstream chemokines interferon-inducible protein-10 (IP-10) and monokine induced by IFN-gamma. Individually, vasostatin and IL-12 produced distinct efficacy profiles in trials aimed at reducing tumor growth in athymic mice. In combination, these inhibitors halted the growth of human Burkitt lymphoma, colon carcinoma, and ovarian carcinoma. Thus, cancer therapy that combines distinct inhibitors of angiogenesis is a novel, effective strategy for the experimental treatment of cancer. (Blood. 2000;96:1900-1905)
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PMID:Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. 1096 92

The presence of "mosaic" vessels in which both endothelial cells and tumor cells form the luminal surface has profound implications for metastasis, drug delivery, and antivascular therapy. Yet little is known of the frequency, and thus importance, of mosaic vessels in tumors. Using CD31 and CD105 to identify endothelial cells and endogenous green fluorescent protein labeling of tumor cells, we show that approximately 15% of perfused vessels of a colon carcinoma xenografted at two different sites in mice were mosaic vessels having focal regions where no CD31/CD105 immunoreactivity was detected and tumor cells appeared to contact the vessel lumen. These regions occupied approximately 25% of the perimeter of the mosaic vessels, or approximately 4% of the total vascular surface area in these colon carcinomas. In addition, we found similar numbers of mosaic vessels in human colon carcinoma biopsies. Our results are consistent with the observation that approximately 10(6) cells are shed daily per g of tumor. More importantly, our data offer a possible explanation for the antivascular effects of cytotoxic agents and suggest potential strategies for targeting the tumor vasculature.
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PMID:Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. 1120 44

Integrin alpha(v)beta(3) is expressed by newly formed blood vessels in diseased and neoplastic tissue and can therefore be used as a marker for angiogenesis. We investigated its expression on the vasculature of 40 colon carcinomas using the anti-alpha(v)beta(3)-specific monoclonal antibody LM609. The average relapse-free interval and overall survival in patients suffering from colon carcinomas with high vascular expression of alpha(v)beta(3) integrin was significantly reduced compared with that in patients with low alpha(v)beta(3) integrin expressing tumor vasculature. Moreover, the expression level of alpha(v)beta(3) integrin correlated with the presence of liver metastases. In conclusion, we propose vascular expression of alpha(v)beta(3) integrin as a prognostic indicator for colon carcinoma.
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PMID:Integrin alpha(v)beta(3) expression in colon carcinoma correlates with survival. 1170 74

The induction of a CTL response capable of eradicating disseminated tumor metastases and the establishment of a persistent tumor-protective immunity remain major goals of cancer immunotherapy. Here, we demonstrate for the first time that the combination of interleukin 2 (IL-2) targeted to the tumor microenvironment by a recombinant antibody-IL-2 fusion protein (huKS1/4-IL-2) with gene therapy by the murine chemokine MIG (CXCL9) markedly reduced s.c. tumor burden and decisively suppressed dissemination of experimental lung metastases of CT26-KSA colon carcinoma in syngeneic BALB/c mice. This combined therapy significantly prolonged the life span of these mice 3-4-fold by concurrently delivering MIG and IL-2 to the tumor site and thereby achieving chemoattraction of T cells together with their activation. The antitumor effect obtained was mediated predominantly by MHC class I antigen-restricted CD8(+) T cells with help from MHC class II antigen-restricted CD4(+) T lymphocytes. In addition, the MIG chemokine also induced angiostatic effects in the tumor vasculature. Taken together, this combination of MIG chemokine gene therapy with tumor-targeted cytokine IL-2 provides an approach for the rational design of novel cancer immunotherapy modalities.
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PMID:MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma. 1173 34

Colon carcinomas frequently express the epidermal growth factor receptor (EGFR), and this expression correlates with more aggressive disease and poor prognosis. Previous studies have shown that EGFR blockade by monoclonal antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these tumors in athymic mice. In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice. IMC-C225 was tested at a dose of 1 or 0.5 mg administered q3d. CPT-11 was administered at a dose of 100 mg/kg/week or a maximum tolerated dose of 150 mg/kg/week. Treatment with the combination of IMC-C225 (1 and 0.5 mg) and CPT-11 (100 mg/kg) significantly inhibited the growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (P < 0.05). Combination therapy with IMC-C225 (1 mg) and the MTD of CPT-11 (150 mg/kg) resulted in a regression rate of 100 and 60% of established DLD-1 and HT-29 tumors, respectively. In a refractory tumor model, combined treatment with IMC-C225 and CPT-11 significantly inhibited the growth of CPT-11 refractory DLD-1 and HT-29 tumors, whereas either agent alone did not control tumor growth. Histological examination of treated tumors showed extensive tumor necrosis, decreased tumor cell proliferation, increased tumor cell apoptosis, and a marked decrease in tumor vasculature. These results suggest that EGFR blockade by IMC-C225 combined with topoisomerase I inhibitors may be an effective therapy against chemorefractory colorectal carcinoma tumors.
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PMID:Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. 1200 11

Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.
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PMID:A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. 1245 72

Angiogenesis is a key process in the growth and metastasis of a tumor. Disrupting this process is considered a promising treatment strategy. Therefore, a drug delivery system specifically aiming at angiogenic tumor endothelial cells was developed. Alpha v beta 3-integrins are overexpressed on actively proliferating endothelium and represent a possible target. For this, RGD-peptides with affinity for this integrin were coupled to the distal end of poly(ethylene glycol)-coated long-circulating liposomes (LCL) to obtain a stable long-circulating drug delivery system functioning as a platform for multivalent interaction with alpha v beta 3-integrins. The results show that cyclic RGD-peptide-modified LCL exhibited increased binding to endothelial cells in vitro. Moreover, intravital microscopy demonstrated a specific interaction of these liposomes with tumor vasculature, a characteristic not observed for LCL. RGD-LCL encapsulating doxorubicin inhibited tumor growth in a doxorubicin-insensitive murine C26 colon carcinoma model, whereas doxorubicin in LCL failed to decelerate tumor growth. In conclusion, coupling of RGD to LCL redirected these liposomes to angiogenic endothelial cells in vitro and in vivo. RGD-LCL containing doxorubicin showed superior efficacy over non-targeted LCL in inhibiting C26 doxorubicin-insensitive tumor outgrowth. Likely, these RGD-LCL-doxorubicin antitumor effects are brought about through direct effects on tumor endothelial cells.
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PMID:Anti-tumor efficacy of tumor vasculature-targeted liposomal doxorubicin. 1293 43

The following study examines the feasibility of nanoshell-assisted photo-thermal therapy (NAPT). This technique takes advantage of the strong near infrared (NIR) absorption of nanoshells, a new class of gold nanoparticles with tunable optical absorptivities that can undergo passive extravasation from the abnormal tumor vasculature due to their nanoscale size. Tumors were grown in immune-competent mice by subcutaneous injection of murine colon carcinoma cells (CT26.WT). Polyethylene glycol (PEG) coated nanoshells (approximately 130 nm diameter) with peak optical absorption in the NIR were intravenously injected and allowed to circulate for 6 h. Tumors were then illuminated with a diode laser (808 nm, 4 W/cm2, 3 min). All such treated tumors abated and treated mice appeared healthy and tumor free >90 days later. Control animals and additional sham-treatment animals (laser treatment without nanoshell injection) were euthanized when tumors grew to a predetermined size, which occurred 6-19 days post-treatment. This simple, non-invasive procedure shows great promise as a technique for selective photo-thermal tumor ablation.
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PMID:Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles. 1515 19

Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/35 may be useful in anticancer strategies targeting tumor endothelial cells.
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PMID:Efficient infection of tumor endothelial cells by a capsid-modified adenovirus. 1610 61


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